This phase I STTR application provides the technical basis for the commercial development of glycation inhibitors as novel protective agents against pathological skin conditions characterized by increased glycation damage. Glycation, the spontaneous reaction of cellular constituents with reducing sugars and other reactive carbonyl species (RCS), has been identified as a key source of endogenous chemical damage contributing to pathologies such as diabetes, atherosclerosis, cancer metastasis, and chronological aging. Academic and commercial research aims towards the development of pharmacological inhibitors of glycation, but no therapeutic approaches have focused on skin as a key target of glycation even though skin is an important target tissue for glycation pathology. Recently, alpha-amino-beta-mercapto-beta,beta-dimethyl-ethane was identified and patented as potent glycation inhibitor pharmacophore, protecting cultured human skin cells against glycation damage. Using this prototype pharmacophore the feasibility of designing topical glycation inhibitors for the therapeutic suppression of glycation damage in skin originating from metabolic deterioration, UV-irradiation, and chronological aging will be examined. The synthesis of ester-derivatives of the prototype glycation inhibitor with optimized lipophilicity for topical skin delivery (specific aim 1) will be followed by the demonstration of protection against glycation damage in reconstructed human skin under acute carbonyl and actinic stress (specific aim 2).